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Auckland, New Zealand

Lau G.K.K.,University of Hong Kong | Kao J.-H.,National Taiwan University Hospital | Gane E.,New Zealand Liver Transplant Unit
Digestive Diseases and Sciences | Year: 2010

Background Replication of hepatitis B virus (HBV) is the primary driver of disease progression and clinical outcomes in patients with chronic hepatitis B (CHB), but other factors, such as hepatitis B e antigen (HBeAg) status, also influence disease course. The importance of HBeAg seroconversion is underscored by current CHB treatment guidelines that recommend limiting the duration of antiviral therapy in HBeAg-positive patients who achieve seroconversion. Aims A 2-day meeting of leading hepatologists with extensive experience managing patients with CHB in the Asia-Pacific region was held with the overall goals of reviewing and evaluating (1) available data on the relationship between HBeAg seroconversion and clinical outcomes for patients with HBeAg-positive CHB, and (2) the ways in which seroconversion should influence patient management. Conclusions It was agreed that HBeAg seroconversion is an important serologic end point for patients with CHB and that achieving this goal should be an important consideration in treatment selection. Patients with HBeAg-positive CHB should consider pegylated interferon if they are aged <40 years (especially women), have lower HBV DNA levels, can afford this treatment, and have a lifestyle that would support adherence to injection therapy. Alternatively, ucleos(t)ide analogs are recommended in patients with alanine aminotransferase levels ≥2 × the upper limit of normal, HBV DNA levels <9 log10 IU/ml, and compensated CHB. Entecavir, telbivudine, and tenofovir may be used as first-line therapy; they can be administered as a finite therapeutic course in HBeAg-positive patients who seroconvert. Telbivudine and tenofovir should be considered in women of child-bearing potential. © Springer Science+Business Media, LLC 2010.

Gane E.J.,New Zealand Liver Transplant Unit | Agarwal K.,Kings College
American Journal of Transplantation | Year: 2014

Chronic hepatitis C virus (HCV) is the leading cause of liver transplantation (LT) in adults. However, infection of the allograft is universal and associated with reduced graft and patient survival. Although successful eradication improves posttransplant outcome, current antiviral therapies have poor efficacy and tolerability. Direct acting antiviral agents (DAAs) provide new opportunities for treatment of HCV recurrence. The addition of a first-generation NS3/4A protease inhibitor (PI) has increased the efficacy of pegylated interferon and ribavirin in patients with chronic HCV genotype 1 infection. Preliminary efficacy results from open-labeled studies of PI-based triple therapy in LT recipients are encouraging. However, the tolerability of triple therapy is reduced following LT, because of increased anemia and drug-drug interactions. The use of PI-based triple therapy in LT recipients seems best suited to larger centers, experienced with management of PI toxicity. Fortunately, other classes of DAAs targeting different steps of HCV replication are in clinical trials, including nucleotide polymerase (NUC-NS5B) inhibitors, nonnucleotide polymerase (non-NUC-NS5B) inhibitors and NS5A inhibitors. Several dual and triple DAA regimens are in clinical development. Phase II studies conducted in patients before and after LT suggest that these regimens will dramatically reduce the impact of recurrent HCV. There is a tide in the affairs of men. Which, taken at the flood, leads on to fortune (Shakespeare: J Caesar Act 4, scene 3) This article reviews direct-acting antiviral agents that improve the safety and efficacy of hepatitis C virus treatment before and after liver transplantation. © Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.

Gane E.J.,New Zealand Liver Transplant Unit | Stedman C.A.,University of Otago | Hyland R.H.,Gilead Sciences Inc. | Ding X.,Gilead Sciences Inc. | And 5 more authors.
Gastroenterology | Year: 2014

Background & Aims We evaluated an all-oral regimen comprising the nucleotide polymerase inhibitor sofosbuvir (SOF) with the NS5A inhibitor ledipasvir (LDV) or the NS5B non-nucleoside inhibitor GS-9669 in patients with genotype 1 hepatitis C virus (HCV) infection. Methods A total of 113 patients were enrolled. Sofosbuvir (400 mg once daily) and LDV (90 mg once daily) plus ribavirin (RBV) were given for 12 weeks to treatment-naïve (TN) patients (n = 25) and those who did not respond to previous therapy (prior null responders, n = 9). Sofosbuvir and GS-9669 (500 mg once daily) plus RBV were given for 12 weeks to TN patients (n = 25) and prior null responders (n = 10). Additionally, prior null responders with cirrhosis were randomly assigned to groups given a fixed-dose combination of SOF and LDV, with RBV (n = 9) or without RBV (n = 10). Finally, a group of TN patients received SOF, LDV, and RBV for 6 weeks (n = 25). The primary efficacy end point was sustained virologic response 12 weeks after therapy (SVR12). Results SVR12 was achieved by 25 of 25 (100%) TN patients receiving SOF, LDV, and RBV and 23 of 25 (92%) of those receiving SOF, GS-9669, and RBV. Of TN patients receiving 6 weeks of SOF, LDV, and RBV, 17 of 25 (68%) achieved SVR12. All noncirrhotic prior null responders receiving 12 weeks of SOF along with another direct-acting antiviral agent plus RBV achieved SVR12 - 9 of 9 (100%) of those receiving SOF, LDV, and RBV and 10 of 10 (100%) of those receiving SOF, GS-9669, and RBV. Among cirrhotic prior null responders, SVR12 was achieved by 9 (100%) of those receiving SOF, LDV, and RBV and 7 (70%) of those receiving SOF and LDVD without RBV. The most common reported adverse events were headache, fatigue, and nausea. Conclusions The combination of SOF and a second direct-acting antiviral agent is highly effective in TN patients with HCV genotype 1 infection and in patients that did not respond to previous treatment. ClinicalTrials.gov ID NCT01260350. © 2014 by the AGA Institute.

Gane E.J.,New Zealand Liver Transplant Unit | Patterson S.,Liver Transplant Unit | Strasser S.I.,rrow Gastroenterology And Liver Center | McCaughan G.W.,rrow Gastroenterology And Liver Center | Angus P.W.,Liver Transplant Unit
Liver Transplantation | Year: 2013

Without effective prophylaxis, liver transplantation for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. Combination prophylaxis with hepatitis B immune globulin (HBIG) and lamivudine (LAM) reduces long-term recurrence rates below 10%; however, HBIG is costly and inconvenient to administer. We, therefore, conducted a multicenter, prospective study of outcomes with an HBIG-sparing regimen of LAM plus adefovir dipivoxil (ADV) initiated at the time of listing for liver transplantation and continued after transplantation. Twenty-six patients were recruited into this study at the time of listing for transplantation, and 20 subsequently underwent transplantation. Twelve of the 26 patients had LAM exposure before the study baseline, but none had LAM resistance. The median HBV viral load before the institution of antiviral therapy was approximately 4.0 log10 IU/mL (range=2.3-7.5 log 10 IU/mL). To the 20 patients who underwent transplantation, 800 IU of intramuscular HBIG was given immediately after transplantation and daily for 7 days only (total HBIG dose=6400 IU). All transplant patients remained alive without HBV recurrence (they were negative for hepatitis B surface antigen, and HBV DNA was undetectable) after a median follow-up of 57 months after transplantation (range=27-83 months). The median serum creatinine level in these patients rose from 81 to 119 μmol/L over the course of the study. No patient required dose reduction or cessation. After the completion of this prospective study, the regimen was modified so that no perioperative HBIG was administered if the pretransplant serum HBV DNA level was suppressed below 3 log10 IU/mL. Another 28 patients with HBV-related liver disease underwent transplantation (18 without HBIG). All remained alive and well without HBV recurrence after a median follow-up of 22 months after transplantation (range=10-58 months). In conclusion, a combination of LAM and ADV initiated at the time of wait listing provides safe and effective protection against recurrent HBV infection without the high costs and inconvenience associated with long-term HBIG therapy. © 2013 AASLD. Copyright © 2013. American Association for the Study of Liver Diseases.

Gane E.J.,New Zealand Liver Transplant Unit
American Journal of Transplantation | Year: 2012

Recurrent hepatitis C virus (HCV) infection of the allograft occurs universally following liver transplantation. Longitudinal natural history studies have identified several pre- and posttransplant factors associated with more rapid fibrosis progression, including baseline host and viral factors, donor factors and posttransplant immunosuppression effects, such as metabolic syndrome. Evidence accumulated over the past two decades indicates that HCV has metabolic associations, in particular insulin resistance and diabetes mellitus. Approximately half of HCV-positive liver transplant recipients develop posttransplant diabetes mellitus (PTDM), which is associated with accelerated fibrosis progression and poorer graft and patient survival outcomes. This review summarizes the risks and consequences of insulin resistance and PTDM in HCV-positive liver transplant recipients. Risk for developing PTDM is one factor that should be considered when choosing the primary immunosuppressive regimen following liver transplantation. Comparative studies suggest that cyclosporine A-based immunosuppression may provide improved responses to antiviral therapy and reduced incidence of PTDM compared with tacrolimus-based immunosuppression. Addressing insulin resistance and PTDM in HCV-positive liver transplant recipients may have the potential to slow HCV complications and improve survival outcomes. Prevention and treatment of posttransplant diabetes mellitus might improve outcomes in hepatitis C virus-positive liver transplant recipients. © copyright 2011 The American Society of Transplantation and the American Society of Transplant Surgeons.

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